Lenalidomide, bortezomib, and dexamethasone (RVd) ± autologous stem cell transplantation (ASCT) and R maintenance to progression for newly diagnosed multiple myeloma (NDMM): The phase 3 DETERMINATION trial.
Authors: Paul G. Richardson, Susanna J. Jacobus, Edie Weller, Hani Hassoun, Sagar Lonial, Noopur S. Raje, Eva Medvedova, Philip L. McCarthy, Edward N. Libby, Peter M. Voorhees, Robert Z. Orlowski, Larry D. Anderson, David D. Hurd, Marcelo C. Pasquini, Kelly Masone, Philippe Moreau, Herve Avet-Loiseau, Michel Attal, Kenneth Carl Anderson, Nikhil C. Munshi
Journal: Journal of Clinical Oncology (2022)

LBA4 Background: Optimal use of triplet/quadruplet induction, ASCT, and R-based maintenance in patients (pts) with NDMM who are eligible for transplant continues to evolve. The IFM 2009 trial, which used R maintenance for 1 year (y), showed progression-free survival (PFS; median, 35.0 vs. 47.3 months [mos]) but no overall survival benefit (OS; 60 vs. 62% at 8 y; median follow-up, 89.8 mos) with RVd + ASCT vs. RVd alone in the setting of multiple effective options at relapse, including ASCT at first relapse in 77% of pts (Attal M et al, N Engl J Med 2017; Perrot A et al, ASH 2020). We report primary data from our US DETERMINATION trial, which used R maintenance until progression. Methods: Pts with NDMM aged 18-65 y were randomly assigned to receive 3 RVd cycles, stem cell mobilization, and then 5 more RVd cycles (Arm A) or IV melphalan 200 mg/m 2 + ASCT and 2 RVd cycles (Arm B). Each 21-d RVd cycle comprised PO R 25 mg (d 1-14), IV/SC bortezomib 1.3 mg/m 2 (d 1, 4, 8, 11), and PO dexamethasone 20/10 mg (cycles 1-3/≥ 4; d 1, 2, 4, 5, 8, 9, 11, 12). Both arms received R 10-15 mg/d maintenance until progression or intolerance. The primary endpoint was PFS (90% power to detect PFS hazard ratio [HR] of 1.43 [Arm A vs. B] with α = 0.05 on stratified two-sided log-rank test; full information: 329 events in 720 pts). Data cut-off was Dec 10, 2021. Results: 357 and 365 pts were randomly assigned to Arms A and B, respectively; median age was 57 and 55 y, 14% and 13% had ISS stage III MM, and 18% each had high-risk cytogenetics [t(4;14), t(14;16), del17p]. In the respective arms, 291 and 290 pts received R maintenance for a median duration of 36 and 41 mos. After median follow-up of 76 mos and 328 events, median PFS was 46.2 vs. 67.6 mos in Arm A vs. B (HR 1.53; 95% CI, 1.23–1.91; p &lt; .0001). Best responses in pts assessed to date were 52 vs. 62% ≥ CR (p = .006), 79 vs. 83% ≥ VGPR and 94 vs. 96% ≥ PR; in 251 evaluable pts, rate of MRD negativity (10 -5 ) was 37.3 vs. 52.1% (p = .021) within 1 y of maintenance. 63 vs. 53% of pts have received subsequent treatment; of Arm A, 22% had ASCT as first non-protocol therapy. With 90 vs. 88 pts having died in Arm A vs. B, 4-y OS was 84% (95% CI, 80–88%) vs. 85% (95% CI, 81–88%); HR 1.10 (95% CI, 0.81–1.47; p = .274). Grade ≥ 3 related adverse events were less common in Arm A vs. B (78 vs. 94%; hematologic: 61 vs. 90%, p &lt; .0001); 10 vs. 11% had secondary malignancies (ALL, 7 vs. 3 pts, p = .22; AML/MDS, 0 vs. 10 pts, p = .002). Difference in mean change from baseline in EORTC QLQ-C30 global health status score was &lt; 10 points throughout treatment except at RVd cycle 5 vs. post-ASCT (compliance rate, 75% vs. 55%; mean change +3.0 vs. –11.1; p &lt; .0001). Whole-genome sequencing, additional QOL, and correlative analyses are ongoing. Conclusions: RVd ± ASCT and R maintenance to progression resulted in the longest median PFS reported for each approach, and a highly significant 21.4-mo gain in median PFS benefit using RVd + ASCT. No OS advantage has been observed to date. Clinical trial information: NCT01208662.